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Novel Anti-hepatitis b virus antibody and uses thereof

a technology of hepatitis b virus and anti-hepatitis b virus, which is applied in the field of molecular virology and immunology, can solve the problems of low clinical efficacy, low price, and less sources of high-potency plasma

Pending Publication Date: 2022-07-28
XIAMEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is an antibody that can specifically recognize, bind to, and neutralize the virulence of HBV. It can also reduce the serum level of HBV DNA and / or HBsAg in the subject and effectively eliminate HBV and HBV-infected cells in the body. This antibody has enhanced antigen clearance and suppression time, making it suitable for preventing and treating HBV infection and diseases associated with HBV infection. It also has pH-dependent antigen binding properties, meaning a single molecule of antibody can bind to multiple molecules of antigens, which can reduce the frequency and dosage of administration. This antibody has great clinical value.

Problems solved by technology

However, the treatment with the above-mentioned drugs alone or in combination cannot completely eliminate the HBV virus in the infected persons, and the response rate of HBsAg negative conversion or HBsAg seroconversion (a sign of complete HBV virus clearance in the infected person) caused thereby is usually less than 5% (Kwon H et al., ibid.).
Currently, there is no definitely significant and effective active immunotherapy drug / vaccine that can be used to treat chronic HBV infection.
However, the direct application of HBIG in the treatment of HBV-infected patients (for example, CHB patients) has no obvious effect, and it has many limitations such as fewer sources for high-potency plasma, high price, unstable nature, and potential safety issues.

Method used

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  • Novel Anti-hepatitis b virus antibody and uses thereof
  • Novel Anti-hepatitis b virus antibody and uses thereof
  • Novel Anti-hepatitis b virus antibody and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

eening of pH-Dependent Anti-HBsAg Antibody

[0193]1.1 Determination of Mutation Site for pH-Dependent Antibody Modification

[0194]The anti-HBV humanized antibody M1D (described in detail in Chinese Patent Application 201810307136.5) previously developed in the laboratory was used as the parent antibody, its variable regions were modified for pH-dependent antigen binding. As shown in FIG. 1, the modified M1D could maintain the antigen-binding activity under neutral conditions, but had a significant decrease in antigen-binding activity under acidic conditions; the dissociated modified M1D could bind to intracellular FcRn so as to return to the plasma and bind to antigen again, so that one molecule of M1D after pH-dependent antigen binding modification could repeatedly bind to and neutralize a plurality of molecules of antigens. Histidine could be protonated under acidic conditions and was a key amino acid to bring pH-dependent antigen binding properties. The three-dimensional structure o...

example 2

on of pH-Dependent Anti-HBsAg Antibody

[0200]2.1 Construction of Recombinant Vector for Eukaryotic Expression

[0201]In the present invention, a large amount of antibody recombination needed to be carried out, so it was necessary to construct a set of light and heavy chain vectors that can efficiently recombine antibodies. In the present invention, the existing eukaryotic expression vector pTT5 in the laboratory was specially modified to construct a set of light and heavy chain recombinant vectors for double plasmid co-transfection. MGWSCIILFLVATATGVHS (SEQ TD NO: 49) was used as the signal peptide for the light and heavy chains. The sequences encoding the constant regions of the human antibody light and heavy chains were separately ligated to the downstream of signal peptide to construct a set of eukaryotic expression vectors pTT5-CH, pTT5-Cκ and pTT5-Cλ that facilitated antibody recombination.

[0202]The four scFv antibodies obtained in 1.3 were used to amplify the light and heavy chai...

example 3

Analysis and Functional Evaluation of pH-Dependent Anti-HBsAg Antibodies

[0208]The 4 strains of phage antibodies with property of pH-dependent binding to HBsAg that were obtained through the preliminary screening by the method of Example 1 were named as A31-73, A42-13, A42-23 and A41-8, respectively. Furthermore, the four strains of phage antibodies were subjected to the eukaryotic expression and purification by the method of Example 2. The VH and VL amino acid sequences of the four antibodies were shown in the table below. In addition, the CDR sequences of the four antibodies were determined, and the amino acid sequences of the CDRs of the heavy chain variable regions and the light chain variable regions were shown in Table 5. The mutation sites that endowed A31-73, A42-13, A42-23 and A41-8 with the property of pH-dependent antigen-binding to HBsAg were summarized in Table 5.

TABLE 4Amino acid sequences of A31-73 / A42-12 / A42-23 / A41-8 lightand heavy chain variable regionsSequenceSEQ ID...

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Abstract

Disclosed are antibodies to anti-hepatitis B surface antigen (HBsAg) (especially humanized antibodies), nucleic acid molecules encoding same, methods for preparing same, and pharmaceutical compositions containing same. The antibodies have higher affinity for HBsAg at neutral pH than at acidic pH, thereby significantly enhancing the virus clearance efficiency and prolonging the virus inhibition time. The antibodies and the pharmaceutical compositions can be used for preventing and / or treating HBV infections or diseases related to HBV infections (e.g., hepatitis B), for neutralizing the virulence of HBV in a subject (e.g., a human), for reducing the serum level of HBV DNA and / or HBsAg in the body of the subject, or for activating the humoral immune response of the subject (e.g., a chronic HBV infected or chronic hepatitis B patient) against HBV.

Description

TECHNICAL FIELD[0001]The present invention relates to the field of molecular virology and immunology, especially the field of treatment of hepatitis B virus (HBV) infection. Specifically, the present invention relates to an antibody against hepatitis B virus surface antigen (HBsAg) and a nucleic acid encoding the antibody, and a use thereof. The anti-HBsAg antibody of the present invention has a higher binding affinity for HBsAg at neutral pH than at acidic pH. The novel antibody can be used for the prevention and / or treatment of an HBV infection or a disease associated with HBV infection (for example, hepatitis B), for neutralizing a virulence of HBV in a subject (for example, a human), or for reducing a serum level of HBV DNA and / or HBsAg in a subject. Therefore, the present invention further relates to a use of the antibody and variant thereof in the manufacture of a pharmaceutical composition for the prevention and / or treatment of an HBV infection or a disease related to an HBV ...

Claims

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Application Information

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IPC IPC(8): C07K16/08A61P31/20
CPCC07K16/082A61P31/20C07K2317/92C07K2317/56C07K2317/515C07K2317/565A61P1/16A61K2039/505C12N15/85C07K2317/24C12P21/02C07K2317/30C07K2317/622C07K2317/72G01N33/5764A61P31/12A61K2039/575C07K2317/52C07K2317/567C07K2317/76
Inventor LUO, WENXINWEN, CANXIANG, XINCHUTANG, JIXIANWU, YANGTAOZHANG, TIANYINGYUAN, QUANXIA, NINGSHAO
Owner XIAMEN UNIV
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